Structure-function relationships for analogues of L-2-amino-4-phosphonobutanoic acid on the quisqualic acid-sensitive AP4 receptor of the rat hippocampus.

Hippocampal CA1 pyramidal cell neurons are sensitized to depolarization by L-2-amino-4-phosphonobutanoic acid (L-AP4) following exposure to L-quisqualic acid (QUIS). We have examined the interaction of 43 structural analogues of L-AP4 with both the 'induction' site and the QUIS-sensitive AP4 site in rat hippocampus. The synthesis of cis- and trans-4-phosphonoxy-L-proline, 3-(RS)-amino-5-phosphonopentanoic acid and 2(RS)-amino-5-phenyl-4(RS)-phosphonopentanoic acid (gamma-benzyl AP4) are described. None of the test compounds interact with the induction site; thus L-QUIS remains the only compound known to induce this effect. However, one compound (L-2-amino-3-(5-tetrazolyl)-propanoic acid (L-aspartate tetrazole) 'pre-blocked' and reversed the effects of QUIS. In addition, the potency of 16 analogues increased more than 4-fold following exposure of slices to L-QUIS. Among these, L-AP4, L-AP5, 2-amino-4-(methylphosphino)butanoic acid (AMPB), and E-1(RS)-amino-3(RS)-phosphonocyclopentanecarboxylic acid (E-cyclopentyl AP4) displayed IC50 values of less than 0.100 mM after QUIS. The results presented here suggest that the QUIS-sensitive AP4 site requires a spatial configuration of functional groups similar to that present in E-cyclopentyl AP4. The presence of a primary amino group and a phosphorus-containing group (either monoanionic or dianionic) appear to be required, however, a carboxyl group is not essential for interaction. The pharmacology of the QUIS-sensitive AP4 site suggests that it is distinct from other known binding sites for L-AP4 in the central nervous system (CNS).